Regulation of FRTL-5 cells, a continuous strain of rat thyroid cells, involves both cyclicAMP and calcium as second messengers. TSH uses both pathways, while alpha 1-adrenergic agents utilize only a calcium signal. Efflux of iodide into the follicular lumen of the thyroid and iodination of thyroglobulin, essential steps in thyroid hormone formation, are regulated by TSH and adrenergic agonists (such as norepinepharine) through calcium mobilization. The transducing mechanism for generation of this second messenger is the phosphodiesterase-mediated hydrolysis of membrane phosphoinositides, in particular phospatidylinositol 4.5 bisphosphate. The products of this cleavage are inositol trisphosphate, which releases calcium form intracellular storage sites, and diacyglcerol which is important in phospholipase C activation and cell growth. Stimulated metabolism of membrane phosphoinositides is also associated with release of arachidonic acid, metabolities of which are implicated in iodide efflux and growth. Thiocyanate, a goitrogen for humans, competes for the transport and metabolism of iodine by the thyroid. Thiocyanate reacts with tyrosyl residues of thyroglobulin in the region where thyroid hormone activity is segregated, with release of a thiocyanate containing peptide. Thyroglobulin isolated from iodine deficient goiters, and an animal with spontaneous goiter, suggest that thyroglobulin related proteins are involved in hormone release and the pathogenesis of iodine deficient goiter. The work continues to support the hypothesis that alterations in ion fluxes are important early events, as well as primary actions of thyrotropin and pharamcologic agents.